The impact of stress on cancer immunotherapy: from mechanistic insights to intervention strategies

BACKGROUND: Immunotherapy has achieved significant breakthroughs in cancer treatment, but its clinical efficacy remains limited in many patients. Concurrently, epidemiological studies indicate that many cancer patients suffer from mental and emotional stress, which may suppress antitumor immunity and weaken immunotherapy efficacy. AIM OF REVIEW: While existing literature predominantly focuses on how stress promotes general tumor progression by remodeling the local tumor microenvironment (TME), a critical knowledge gap remains regarding its specific impact on immunotherapy. To complement this line of research, this review aims to bridge this gap by explicitly shifting the focus to how stress compromises cancer immunotherapy. It expands the analytical perspective from purely localized tumor niches to the systemic immune macroenvironment to propose mechanistically-driven intervention strategies. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review systematically dissects how the sympathetic nervous system (SNS), hypothalamic-pituitary-adrenal (HPA) axis, and diverse neurometabolites impair therapeutic efficacy. Mechanistically, it details how these neuroendocrine pathways induce local immunosuppression within the TME and drive systemic immune dysregulation. Crucially, the review highlights how stress-induced dysfunction in immune organs (e.g., bone marrow, thymus, and spleen) and distant non-immune organs (e.g., liver and intestines) collectively compromises cancer immunotherapy. Finally, strategies targeting these pathways are proposed to potentiate immunotherapy efficacy. An emphasis is placed on personalized combination therapies that integrate pharmacological and behavioral interventions aimed at synergizing with immune checkpoint inhibitors, thereby providing novel insights for future research.